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Safety Data

Safety Data

ENHERTU has serious Warnings and Precautions. Click here for information related to monitoring for and management of ILD/pneumonitis. Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

ENHERTU has serious Warnings and Precautions. Click here for information related to monitoring for and management of ILD/pneumonitis. Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

In activating HER2-mutant 2L mNSCLC at 5.4 mg/kg

The majority of adverse reactions observed with ENHERTU were Grade 21

Only the results for the recommended dose of 5.4 mg/kg are described due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.1

  • 19% of the 101 patients treated with ENHERTU in DESTINY-Lung02 were exposed for >6 months1
  • The cutoff date for safety data was March 24, 20222

Common (10% all Grades or 2% Grades 3-4) adverse reactions in DESTINY-Lung021

Adverse reactions ENHERTU
5.4 mg/kg (n=101)
All Grades (%) Grades 3 or 4 (%)
Gastrointestinal disorders Nausea 61 3
Constipation 31 1
Vomitinga 26 2
Diarrhea 19 1
Stomatitisb 12 0
Blood and lymphatic system disorders Anemia 34 10
General disorders and administration site conditions Fatiguec 32 4
Metabolism and nutrition disorders Decreased appetite 30 1
Skin and subcutaneous tissue disorders Alopecia 21 0
Musculoskeletal and connective tissue disorders Musculoskeletal paind 15 1
Adverse reactions ENHERTU
5.4 mg/kg (n=101)
All Grades
(%)
Grades 3 or 4
(%)
Gastrointestinal disorders
Nausea 61 3
Constipation 31 1
Vomitinga 26 2
Diarrhea 19 1
Stomatitisb 12 0
Blood and lymphatic system disorders
Anemia 34 10
General disorders and administration site conditions
Fatiguec 32 4
Metabolism and nutrition disorders
Decreased appetite 30 1
Skin and subcutaneous tissue disorders
Alopecia 21 0
Musculoskeletal and connective tissue disorders
Musculoskeletal paind 15 1

Events were graded using NCI-CTCAE v.5.0.

aIncluding vomiting and retching.

bIncluding mucosal inflammation and stomatitis.

cIncluding asthenia, fatigue, and malaise.

dIncluding back pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity.

 

Other clinically relevant adverse reactions reported in <10% of patients in DESTINY-Lung021

  • Respiratory, thoracic, and mediastinal disorders: ILDe (6%), dyspnea (5%), and epistaxis (3%)
  • Gastrointestinal disorders: abdominal painf (9%)
  • Skin and subcutaneous disorders: rashg (3%)
  • Infections and infestations: upper respiratory tract infectionh (4%)
  • Nervous system disorders: headachei (4%)

eIncluding ILD that was adjudicated as drug-induced ILD, including pneumonitis, ILD, pulmonary toxicity, and respiratory failure.

fIncluding abdominal discomfort, abdominal pain, and upper abdominal pain.

gIncluding rash and maculo-papular rash.

hIncluding upper respiratory tract infection, pharyngitis, and laryngitis.

iIncluding headache and migraine.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU1

  • Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I
  • Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%)

Adverse reactions requiring dose discontinuation, interruption, or reduction in DESTINY-Lung021

8% permanent discontinuation
due to adverse reactions

 

Adverse reactions that resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting

23% dose interruption
due to adverse reactions

 

Adverse reactions that required dosage interruption (>2%) included neutropenia and ILD/pneumonitis

11% dose reduction
due to adverse reactions

Selected laboratory abnormalities in patients in DESTINY-Lung021

Laboratory parameter ENHERTU
5.4 mg/kg (n=101)j
All Gradesk (%) Grades 3 or 4k (%)
Hematologyl Decreased white blood cell count 60 4
Decreased hemoglobin 58 10
Decreased neutrophil count 52 12
Decreased lymphocyte count 43 16
Decreased platelet count 40 4
Chemistry Decreased albumin 39 0
Increased aspartate aminotransferase 35 1
Increased alanine aminotransferase 34 2
Increased alkaline phosphatase 22 0
Decreased blood potassium 17 2
Laboratory parameter ENHERTU
5.4 mg/kg (n=101)j
All Gradesk (%) Grades 3 or 4k
(%)
Hematologyl
Decreased white blood cell count 60 4
Decreased hemoglobin 58 10
Decreased neutrophil count 52 12
Decreased lymphocyte count 43 16
Decreased platelet count 40 4
Chemistry
Decreased albumin 39 0
Increased aspartate aminotransferase 35 1
Increased alanine aminotransferase 34 2
Increased alkaline phosphatase 22 0
Decreased blood potassium 17 2

jPercentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.

kFrequencies were based on NCI-CTCAE v.5.0 grade-derived laboratory abnormalities.

lThe denominator used to calculate the rate varied from 98 to 99 based on the number of patients with a baseline value and at least 1 post-treatment value.

 

Drug interaction studies1

  • Effect of CYP3A inhibitors and OATP inhibitors on DXd (clinical studies): There were no clinically meaningful drug-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor) or ritonavir (OATP1B/CYP3A inhibitor)
  • Effect of DXd on CYP enzymes (in vitro studies): DXd did not inhibit common CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A), nor induce CYP1A2, CYP2B6, or CYP3A
  • Effect of DXd on transporters (in vitro studies): At clinically relevant concentrations, DXd has a low potential to inhibit the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP
  • Effect of other drugs on DXd (in vitro studies): DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP

 

2L, second line; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; DXd, deruxtecan; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; MATE, multidrug and toxic compound extrusion; mNSCLC, metastatic non-small cell lung cancer; MRP1, multidrug resistance protein 1; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NSCLC, non-small cell lung cancer; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

  • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
  • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU.

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in DESTINY-Lung02 and other clinical trials. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).

HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)

DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.

The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY-Lung02. Nineteen percent of patients were exposed for >6 months.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).

Use in Specific Populations

  • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
  • Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
  • Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
  • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
  • Geriatric Use: Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
  • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

References
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
  • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
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